Ephedrine oil solution



Patented June 3, 1930 UNITED sTATEs PATENT OFFICE ELMER H. STUART, OF INDIANAPOLIS, INDIANA, ASSIGNOR TO ELI LILLY AND GOM- IPAN'Y, OF INDIANAPOLIS, INDIANA, A CORPORATION OF INDIANA EIPHEDRINE OIL SOLUTION No Drawing. Original application filed February 13, 1929, Serial No. 389,752. Divided and this application filed May 10, 1929. Serial No. 362,119.

It is the object of my invention to produce a solution of ephedrine in oil, and more especially in mineral oil (liquid petrolatum) to do so in a form that will be stable under all ordinary conditions;

I same time to increase the maximum content and a species.

the solution may have of ephedrine, and thus to" make the ephedrine content in the solution larger than would normally be possible in a simple solution in oil under many of those conditions.

The main purpose for producing such a solution of e hedrine in oil is to make the ephedrine eif ctively and conveniently applicable in. the form of an unctuous nasal spray; and to improve the action of the ephedrine on the mucous membrane, as of the nose, and on the patient generally, by insuring that the ephedrine will be retalned on the mucous membrane over a considerable period and that its action will be spread overa greater surface thereof, by prolonging the action of the ephedrine and making its absorption slower but more complete and eflicacious, and by protecting the treated mucous membrane (inflammation of which is often the reason for the treatment) during and following the blanching action of the ephedrine thereon.

This present application is a division of my co-pending application Serial No. 339,- 752, filed February 13, 1929, now Patent No. 1,7 43,992, grant d January 14, 1930. Such co-pending application is directed to the generic invention and to certain sub-genuses This present application is directed to another species of the same generic invention, and involves the use of cer tain suitable di-oxygensubstances, more esaifections, as of the nose, throat, and associated organs. It and its derivatives are fairly soluble in water, and certain other polar solvents. Water solutlons, however, are often undesirable for application to the and at the mucous membrane, as in a nasal spray.

As set forth in my aforesaid parent application, I have discovered that a solution of ephedrine can be made in oil. I have found that such a solution can be made in various oils, such for instance as cottonseed oil; but that a solution of ephedrine with mineral oil (liquid petrolatum) comprising at least the greater part of the solvent or menstruum is especially desirable.

Ephedrine, however, is diflicultly soluble in the various oils ordinarily used as menstruums for nasal sprays, whether such men struums are mineral oils such as para-flin oils, or vegetable oils such as cottonseed or olive oils. Although occasionally a. vegetable oil, such as cottonseed oil, is used as such a menstruum, either by itself or-mixed with a mineral oil, and both the generic invention of the parent application and the specific invention of this present application in their broader aspects are applicable to vegetable oils such as cottonseed oil, the oils which are commonly used as such menstruums are almost always in the main some form of mineral oil or liquid petrolatum; and my invention is more especially applicable in its narrower aspects to such 'Inineral oil. It is to such mineral oils which are suitable for menstruums for nasal sprays that I refer herein in using the term mineral oil. Simple solutions of ephedrine in mineral oil can be made and used for nasal sprays, for ephedrine is slightly soluble in lower temperatures encountered in oflices and dwellings, and is so variable with temperature, that such simple solutions of ephedrine in mineral oil are not the most suitable. Such simple solutions are physically unstable at the lower temperatures which are almost certain to be encountered, if the concentration of ephedrine is made suflicient to betlierapeutically efi'ect-ive.

For example, a 2% solution (by weight) of ephedrine in light parafiin oil, which is a most desirable form of mineral oil for a nasal spray,'can be made by, heating and stirring. This can be effectively used if it is prevented from getting cold; but as it is allowed .to cool below about 68 F., the ephedrine is precipitated to a greater or less'extent, and will return into solution only with difliculty, as by reheating and prolonged shaking. If the temperature is lowered to 32 F., or 0? 0., it is found that most of the ephedrine has been precipitated; for I have found that such a light parafiin oil normally has the capacity for holding in solution materially less than one-half percent of ephedrine at 0 G. Since temperatures of"68 .F. and less are quite common, even in ofiices and homes, and almost inevitable in temperate climates, a simple solution of ephedrine in paraifin oil thus becomes uncertain in' value; because when the solution is used it may be that much of the ephedrine will have been precipitated from it, so that the purported solution is so near to being oil alone that it is not therapeutically active. Even through some ephedrine is retained in solution, its amount is problematical; while if the solution has been made suificiently weak in ephedrine so that there will be no danger of precipitation, the ephedrine content is too small to have any sufficient therapeutic efl'ect.

But as also set forth in my aforesaid parent application, I have also discovered how it is possible to obtain solutions of ephedrine in oil, and especially in mineral oil, that will maintain the ephedrine in solution in a homogeneous system at all temperatures practically encountered-say even until the temperature lowered to the freezing point of waterbefore cloudiness appears in the solution. This makes an ephedrine mineral-oil solution which is entirely practical, instead of one that is impractical under many conditions.

By such invention I can increase the maximum amount of ephedrine which can be held in solution in a fixed vegetable oil, such as cottonseed oil or olive 011; but the principal use of such invention appears to be1 in connection with ephedrine in mineral o1 In obtaining these more desirable results, I use in the solution one or more other organic ingredients besides the oil-usually mainly mineral oiland ephedrine. There are a number of such organic ingredients which are capable of accomplishing the desiredresult, in varying degrees, of holding the ephedrine in solution in the oil even upon lowering of the temperature; as set forth in said parent application.

At least enough of such additional substance or substances should be used to maintain in solution the amount of ephedrine which it is desired the solution shall con tain at the lowest temperature that there is danger of encountering. In practice I enough of 'the additional substance or substances to dissolve or combine with the entire amount of ephedrine which the final oil solution is to contain. The amount needed of the additional substance varies with the substance used, and with the expected minimum temperature, With the substances contemplated by the present divisional application, this requires between one-half and two molecular equivalents of the amount of ephedrine to be used.

The. additional substance which may be used in accordance with the invention of this present application are certain dioxygen substances, and especially an acetal. For instance, I have found that acetal and tertiary butyl acetalare both quite eiiective.

In using them as the additional substance, say to produce a 1% solution of ephedrine in li ht parafiin oil, I desirably use an equal weig t of acetal or tertiary butyl acetal \Vith such proportions I find that the solution remains stable and unclouded-nntil the temperature is lowered to 10 in the case of acet l and to 0 C. in the case of tertiary but 1 acetal. Thesetemperatures are lower than those usually encountered in homes and business oilices; so that solutions thus prepared in mineral oil may be counted on to retain the full amount of ephedrine in solution under all conditions ordinarily encountered. Further, if the temperature should be lowered to such a" point that the ephedrinee is precipitated, the solution is too cold to be used theraputically; and upon warming to a tem perature suitable for use, the ephedrine returns into solution in the presence of the acetal or of the tertiary butyl acetal, although sometimes slight shaking is desirable, instead of requiring it to be heated to temperatures higher than the normal temperatures to be encountered in the home or ofiice.

I claim:

1. A solution of ephedrine in oil, comprising mineral oil, ephedrine as one sub-. stance dissolved therein, and an acetal also dissolved therein.

2. A solution of ephedrine in oil, comprising mineral oil,-ephedrine as one substance dissolved therein, and an acetal also dissolved therein ina proportion by weight at least as great as that of the ephedrine.

3. A solution of ephedrine in oil, comprising mineral oil, ephedrine as one substance dissolvedtherein, and acetal also dissolved therein.

In witness whereof, I have hereunto set my hand at Indianapolis, Indiana, this seventh day of May, A. D. one thousand nine hundred and twenty nine.

' ELMER H. STUART. 

